ArticleMutation research2009
E. coli mismatch repair acts downstream of replication fork stalling to stabilize the expanded (GAA.TTC)(n) sequence.
Article in Mutation research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
3 citing papers in PubMed, 7 citations in OpenAlex.
- Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability.Nature communications · 2024Article
- Genome-wide screen identifies pathways that govern GAA/TTC repeat fragility and expansions in dividing and nondividing yeast cells.Molecular cell · 2012Article
- Progressive GAA.TTC repeat expansion in human cell lines.PLoS genetics · 2009Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Expanded triplet repeat sequences are known to cause at least 16 inherited neuromuscular diseases. In addition to short-length changes, expanded triplet repeat tracts frequently undergo large changes, often amounting to hundreds of base-pairs. Such changes might occur when template or primer slipping creates insertion/deletion loops (IDLs), which are normally repaired by the mismatch repair system (MMR). However, in prokaryotes and eukaryotes, MMR promotes large changes in the length of (CTG.CAG)(n) sequences, the motif most commonly associated with human disease. We tested the effect of MMR on instability of the expanded (GAA.TTC)(n) sequence, which causes Friedreich ataxia, by comparing repeat instability in wild-type and MMR-deficient strains of Escherichia coli. As expected, the prevalence of small mutations increased in the MMR-deficient strains. However, the prevalence of large contractions increased in the MMR mutants specifically when GAA was the lagging strand template, the orientation in which replication fork stalling is known to occur. After hydroxyurea-induced stalling, both orientations of replication showed significantly more large contractions in MMR mutants than in the wild-type, suggesting that fork stalling may be responsible for the large contractions. Deficiency of MMR promoted large contractions independently of RecA status, a known determinant of (GAA.TTC)(n) instability. These data suggest that two independent mechanisms act in response to replication stalling to prevent instability of the (GAA.TTC)(n) sequence in E. coli, when GAA serves as the lagging strand template: one that is dependent on RecA-mediated restart of stalled forks, and another that is dependent on MMR-mediated repair of IDLs. While MMR destabilizes the (CTG.CAG)(n) sequence, it is involved in stabilization of the (GAA.TTC)(n) sequence. The role of MMR in triplet repeat instability therefore depends on the repeat sequence and the orientation of replication.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.